Browsing by Author "Gerald A. LeBlanc, Committee Chair"

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    Mechanisms through which an environmental antiandrogen, vinclozolin, induces malformations of the male rat reproductive tract.
    (2002-11-25) Wolf, Cynthia Jean; John Vandenbergh, Committee Member; Russell Borski, Committee Member; Stacy Branch, Committee Member; Gerald A. LeBlanc, Committee Chair; L. Earl Gray, Jr., Committee Member
    Androgens activate the androgen receptor (AR) to stimulate transcription of gene products that mediate local control of morphogenesis of the male reproductive tract. The fungicide vinclozolin (V) interferes with male reproductive tract development by antagonizing the AR. In this dissertation research, we investigated whether V also may elicit antiandrogenic effects by suppressing the AR or suppressing epidermal growth factor (EGF) and its receptor. EGF has been implicated as a local contributor to the androgen response. Our first objective was to identify a dosing regime that would reliably interfere with masculine development of exposed male fetuses. Specific demasculinizing effects of V were also evaluated. Administration of V to the rat dam at 200 mg/kg from gestational day (GD) 14 - 19 induced a full array of antiandrogenic effects. Malformations, including cleft phallus, vaginal pouch and ectopic testes, were induced in 97% of the male offspring. V at 400 mg/kg increased the severity of these malformations without inducing overt toxicity. Next, we used this dosing regime (200 mg/kg on GD 14 - 19) to test the hypothesis that co-administration of an androgenic competitor for the AR, testosterone propionate (TP), would antagonize V in vivo and ameliorate its effects. TP attenuated most antiandrogenic effects of V in the male offspring. V attenuated the masculinizing effects of TP in the female. The results indicate that V and androgen TP are competing for occupancy of the AR and can attenuate the effects of the other. We then investigated whether the EGF and the EGF receptor (EGFR) are employed downstream of the AR in androgen action, and are altered by V. First, we tested the hypothesis that EGF is a downstream agent of androgenic action by evaluating whether EGF co-administration during prenatal development would allow normal masculinization of V-treated fetuses. EGF at 20 or 100 micrograms/kg to the dam did not induce androgenic effects or attenuate antiandrogenic effects of V in the offspring. We next tested the hypothesis that AR inhibition by V reduces EGFR expression in affected tissue. We analyzed EGFR expression levels in the fetal phallus exposed to V by immunohistochemistry. EGFR levels were not altered on GD 18 in the male phallus by V exposure. We concluded that EGFR levels do not play a role in initiation of the antiandrogenic effects of V. Lastly, we hypothesized that AR expression is reduced by V in affected tissue immediately following exposure. We analyzed AR expression in weanling and adult sex accessory glands and in the fetal phallus of males exposed to prenatal V. We found that AR expression was not altered in the adult, weanling, or fetus by prenatal V. These results suggest that altered AR expression level is not a mechanism by which V induces antiandrogenic effects. In summary, we have found that prenatal exposure to V produces a variety of permanent antiandrogenic effects in the male rat fetus. These effects can be attenuated with exogenous androgen treatment, which is consistent with the known ability of V to inhibit the AR. No evidence was generated to suggest that V also elicits antiandrogenic activity by suppressing AR levels, or suppressing EGF or EGFR levels. These results do not disprove an association of EGF in AR action. Additional studies are required to definitively establish any putative role of EGF in development of the male reproductive tract.
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    Neonatal Exposure to the Phytoestrogen Genistein Alters Ovarian Differentiation and Development
    (2006-01-17) Jefferson, Wendy Noble; John Vandenbergh, Committee Member; Johh Gadsby, Committee Member; Gerald A. LeBlanc, Committee Chair; Retha R. Newbold, Committee Member; Ida Washington Smoak, Committee Member
    Genistein, the primary phytoestrogen in soy, was investigated for potential adverse effects on the developing female reproductive system with particular focus on the ovary. Mice were treated with genistein at doses that span the range of human exposure including vegetarian mothers during pregnancy and lactation to infants on soy based infant formulas. Neonatal genistein exposure caused the formation of multi-oocyte follicles (MOFs) in the ovary. This effect is mediated by ERβ as mice lacking this receptor do not develop MOFs while mice lacking ERβ do. Further study of genistein's effects on the ovary revealed inhibition of neonatal oocyte nest breakdown; oocytes were still attached by intercellular bridges and the normal progression of apoptosis was attenuated. Mechanistic studies of MOF formation revealed alterations in cell adhesion molecules. In addition, genistein is not unique in its ability to cause ovarian disruption; other environmental estrogens caused MOFs as well as altered cell adhesion molecule expression. Further, these effects appear to be exacerbated by preferential binding to ERβ. Assessment of reproductive function showed that mice treated with genistein (0.5 and 5 mg/kg) showed signs of early reproductive senescence while mice treated with genistein (50 mg/kg) exhibited infertility characterized by fewer, smaller, implantation sites as well as reabsorptions; ovaries from these mice had no corpora lutea. Stimulation with exogenous gonadotropins restored ovulation, suggesting problems with the hypothalamic-gonadal axis. These data taken together demonstrate that neonatal exposure to genistein at environmentally relevant doses causes adverse effects on the developing reproductive system and in particular on the ovary.
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